Compositions and methods for treating otic, ophthalmic and nasal infections

ABSTRACT

Ophthalmic, otic and nasal compositions containing a new class of antibiotics (e.g., moxifloxacin) are disclosed. The compositions preferably also contain one or more anti-inflammatory agents. The compositions may be utilized to treat ophthalmic, otic and nasal conditions by topically applying the compositions to the affected tissues. The compositions and methods of the invention are particularly useful in the treatment of acute otitis externa infections and ophthalmic infections attributable to one or both of two newly identified Microbacterium species,  Microbacterium otitidis  and  Microbacterium alconae.

[0001] The present application is a continuation-in-part based on U.S.application Ser. No. 09/575,850 filed May 19, 2000, which claimspriority to International Application No. PCT/US99/22622 filed on Sep.29, 1999, which claims priority of International Application Ser. No.PCT/US99/22624 filed on Sep. 29, 1999, which claims priority ofInternational Application Ser. No. PCT/US99/22625 filed on Sep. 29,1999.

BACKGROUND OF THE INVENTION

[0002] The present invention is directed to the provision of topicalpharmaceutical compositions for treating otic infections, particularlyacute otitis externa infections caused by two newly discovered bacterialspecies, Microbacterium sp. nov. otitidis and Microbacterium sp. nov.alconae. The present inventors have isolated these species, and havedetermined that these species are pathogens in acute otitis externainfections. The present invention is directed to the provision oftopical pharmaceutical compositions and methods for treating oticinfections that are partially or wholly attributable to these newlydiscovered bacterial species, as well as ophthalmic and nasal infectionswherein these species are acting as pathogens. The compositions andmethods of the present invention are based on the use of quinoloneantibiotics to treat such infections, particularly second and thirdgeneration quinolones, such as gatifloxacin and moxifloxacin,respectively.

[0003] Quinolone antibiotics have been previously utilized to treatophthalmic and otic infections. For example, a topical ophthalmiccomposition containing the quinolone ciprofloxacin is marketed by AlconLaboratories, Inc. under the name CILOXAN™ (Ciprofloxacin 0.3%)Ophthalmic Solution, and a topical otic composition containing acombination of ciprofloxacin and hydrocortisone is marketed by AlconLaboratories, Inc. under the name CIPRO™ HC. The following quinoloneshave also been utilized in ophthalmic antibiotic compositions: QuinoloneProduct Manufacturer Ofloxacin OCUFLOX ™ Allergan NorfloxacinCHIBROXIN ™ Merck Lomefloxacin LOMEFLOX ™ Senju

[0004] The foregoing quinolone antibiotic compositions are generallyeffective in treating ophthalmic infections, and have distinctadvantages over prior ophthalmic antibiotic compositions, particularlythose having relatively limited spectrums of antimicrobial activity,such as: neomycin, polymyxin B, gentamicin and tobramycin, which areprimarily useful against gram negative pathogens; and bacitracin,gramicidin, and erythromycin, which are primarily active against grampositive pathogens. However, despite the general efficacy of theophthalmic quinolone therapies currently available, there is a need forimproved compositions and methods of treatment based on the use ofantibiotics that are more effective than existing antibiotics againstkey ophthalmic pathogens, and less prone to the development ofresistance by those pathogens.

[0005] There is an even greater need for effective topical compositionsand methods for treating otic and nasal infections, particularlybacterial infections. The use of oral antibiotics to treat oticinfections in children has limited efficacy, and creates a serious riskof pathogen resistance to the orally administered antibiotics. Althoughciprofloxacin has proven to be an effective agent in treating oticinfections, there is a need for a better understanding of the etiologyof these infections and a corresponding need for therapies that addressthe causes of these infections more directly and effectively.

[0006] Ophthalmic, otic and nasal infections are frequently accompaniedby inflammation of the infected ophthalmic, otic and nasal tissues andperhaps even surrounding tissues. Similarly, ophthalmic, otic and nasalsurgical procedures that create a risk of microbial infectionsfrequently also cause inflammation of the affected tissues. Thus, thereis also a need for ophthalmic, otic and nasal pharmaceuticalcompositions that combine the anti-infective activity of one or moreantibiotics with the anti-inflammatory activity of one or more steroidor non-steroid agents in a single composition.

SUMMARY OF THE INVENTION

[0007] The invention is based on the use of a potent new class ofantibiotics to treat ophthalmic, otic and nasal infections, as well asthe use of these antibiotics prior to surgery to sterilize the surgicalfield and prophylactically following surgery or other trauma to otic,ophthalmic or nasal tissues to minimize the risk of infection. Thecompositions of the present invention may also be administered to theaffected tissues during otic, ophthalmic or nasal surgical procedures toprevent or alleviate post-surgical infection. As utilized herein, theterms “treat”, “treating” and derivations thereof are intended toinclude both treatments of existing infections and treatments to preventor reduce the risk of infections.

[0008] The compositions preferably also contain one or moreanti-inflammatory agents to treat inflammation associated withinfections of otic, ophthalmic, or nasal tissues. The anti-inflammatorycomponent of the compositions is also useful in treating inflammationassociated with physical trauma to otic, ophthalmic, or nasal tissues,including inflammation resulting from surgical procedures. Thecompositions of the present invention are therefore particularly usefulin treating inflammation associated with trauma to otic, ophthalmic, ornasal tissues wherein there is either an infection or a risk of aninfection resulting from the trauma.

[0009] Examples of ophthalmic conditions that may be treated with thecompositions of the present invention include conjunctivitis, keratitis,blepharitis, dacyrocystitis, hordeolum and corneal ulcers. Thecompositions of the invention may also be used prophylactically inconnection with various ophthalmic surgical procedures that create arisk of infection.

[0010] Examples of otic conditions that may be treated with thecompositions of the present invention include otitis extema and otitismedia. With respect to the treatment of otitis media, the compositionsof the present invention are primarily useful in cases where thetympanic membrane has ruptured or tympanostomy tubes have beenimplanted. The compositions may also be used to treat infectionsassociated with otic surgical procedures, such as tympanostomy, or toprevent such infections.

[0011] The compositions and methods of the present invention areparticularly useful in the treatment of acute infections of the externalear canal, which are commonly referred to as “acute otitis externa” or“AOE”. The present invention is based in part on the isolation of twobacterial species that have not previously been identified as pathogensrelative to acute otitis externa infections. These bacterial species,which have been named “Microbacterium otitidis” and “Microbacteriumalconae”, are described in greater detail below. The present inventionis also based in part on a finding that the quinolone antibioticsutilized in the present invention, particularly third generationquinolones, such as Moxifloxacin, have a very high level ofantimicrobial activity against these newly discovered pathogens, andtherefore are particularly useful in the treatment of acute otitisexterna infections involving these pathogens.

[0012] The two bacterial species that have been identified as beingassociated with acute otitis externa infections have also beendiscovered to be associated with ophthalmic infections. As indicatedabove, the antibiotics utilized in the present invention have a highlevel of antimicrobial activity against these newly discoveredophthalmic pathogens, and as a result, the compositions of the presentinvention are particularly useful in treating ophthalmic infectionsinvolving these species.

[0013] The compositions of the present invention are speciallyformulated for topical application to otic, ophthalmic, and nasaltissues. The compositions are preferably sterile, and have physicalproperties (e.g., osmolality and pH) that are specially suited forapplication to otic, ophthalmic, and nasal tissues, including tissuesthat have been compromised as the result of preexisting disease, trauma,surgery or other physical conditions.

BRIEF DESCRIPTION OF THE DRAWING

[0014] The sole FIGURE of drawings is an automated ribotyping chartshowing the relationships between two newly identified bacterial speciesand other, known species.

DETAILED DESCRIPTION OF THE INVENTION

[0015] The antibiotics used in the compositions and methods of thepresent invention classified as quinolones. The preferred quinolones aresecond generation quinolones, such as Gatifloxacin, and third generationquinolones, such as Moxifloxacin. The designation of quinoloneantibiotics as “second generation” or “third generation” is well knownin the field of antibiotic therapy. This knowledge is reflected innumerous scientific articles, such as: Blondeau, J. M., “A review of thecomparative in-vitro activities of 12 antimicrobial agents, with a focuson five new ‘respiratory quinolones’”, J. of Antimicrobial Chemotherapy,43, Suppl. B. 1-11 (1999); Tillotson, G. S., “Quinolones:structure-activity relationships and future predictions”, J. of MedicalMicrobiology, 44, 320-4 (1996); Wentland, M. P., “Structure-activityrelationships of fluoroquinolones”, In the New Generation of Quinolones,(Siporin, C., Heifetz, C. L. & Domagala, J. M., Eds), pp. 1-43, MarcelDekker, New York (1990); and Gootz, T. D. and Brighty, K. E.,“Fluoroquinolone antibacterials: SAR mechanism of action, resistance,and clinical aspects”, Medicinal Research Reviews 16, 433-86 (1996).These articles provide further details regarding the structure/activityrelationships of quinolone antibiotics and the classification ofquinolones as second generation or third generation.

[0016] The preferred quinolone antibiotics are second generationquinolones, such as Ciprofloxacin, Ofloxacin, Gatifloxacin andGrepafloxacin, and third generation quinolones, such as Moxifloxacin andTrovafloxacin. The third generation quinolones are most preferred.Examples of second and third generation quinolones that may be utilizedin the present invention are provided below.

[0017] The most preferred third generation quinolones are Moxifloxacinand related compounds of the following formula:

[0018] wherein:

[0019] A is CH, CF, CC1, C-OCH₃, or N;

[0020] X¹ is H, halogen, NH₂, or CH₃;

[0021] R¹ is C₁ to C₃ alkyl, FCH₂CH₂, cyclopropyl or phenyl, optionallymono-, di- or tri-substituted by halogen, or A and R₁ together can forma bridge of formula C-O-CH₂-CH(CH₃);

[0022] R² is H, C₁ to C₃ alkyl (optionally substituted by OH, halogen orNH₂), or 5-methyl-2-oxo-1,3-dioxol-4-yl-methyl; and

[0023] B is a selected from the group consisting of:

[0024] wherein:

[0025] Y is O or CH₂;

[0026] R³ is C₂-C₅ alkoxyl, CH₂-CO-C₆H₅, CH₂CH₂CO₂R′, R′O₂C-CH=C-CO₂R′,CH=CH-CO₂R′ or CH₂CH₂-CN,

[0027] wherein:

[0028] R′ is H or C₁ to C₃ alkyl;

[0029] R⁴ is H, C₁ to C₃ alkyl, C₂-C₅ alkoxyl, CH₂-CO-C₆H₅, CH₂CH₂CO₂R′,R′O₂C-CH=C-CO₂R′, CH=CH-CO₂R′, CH₂CH₂-CN or 5-methyl-2-oxo-1,3-dioxol-4-yl-methyl,

[0030] wherein:

[0031] R′ is H or C₁ to C₃ alkyl; and their pharmaceutically usefulhydrates and salts.

[0032] The compound Moxifloxacin is most preferred. Moxifloxacin has thefollowing structure:

[0033] Further details regarding the structure, preparation, andphysical properties of Moxifloxacin and other compounds of formula (I)are provided in U.S. Pat. No. 5,607,942. The contents of U.S. Pat. No.5,607,942 relating to the structure, physical properties, andpreparation of the compounds of formula (I) are hereby incorporated inthe present specification by reference.

[0034] Other third generation quinolones that may be utilized in thepresent invention include Trovafloxacin and related compounds of thefollowing formula:

[0035] wherein

[0036] R1 is hydrogen, a pharmaceutically acceptable cation, or (C1-C6)alkyl;

[0037] Y, when taken independently, is ethyl, t-butyl, vinyl,

[0038] cyclopropyl,2-fluoroethyl,p-fluorophenyl, or o,p-difluorophenyl;

[0039] W is hydrogen, F, C1, Br, C1-C4alkyl, C1-C4 alkoxy, NH2 or NHCH3;

[0040] A is CH, CF, CC1, COCH3, C-CH3, C-CN or N; or

[0041] A is carbon and is taken together with Y and the carbon andnitrogen to which A and Y are attached to form a five or six memberedring which may contain oxygen or a double bond, and which may haveattached thereto R8 which is methyl or methylene;

[0042] and

[0043] R2 is

[0044] wherein:

[0045] R3, R4, R5, R6, R7, R9, R10 and R25 are each independently H,CH3, CH2NH2, CH2NHCH3 or CH2NHC2H5, and R5, R6, R7, and R9 may alsoindependently be NH2, NHCH3 or NHC2H5, provided that not more than threeof R3, R4, R5, R6, R7, R9, R10 and R25 are other than hydrogen, and ifthree of these substituents are not hydrogen, at least one of them ismethyl.

[0046] The antibiotics utilized in the present invention also includeprodrugs of the compounds of formula (II) having a free amino group, aswell as pharmaceutically useful hydrates and salts of the compounds offormula (II).

[0047] The compound Trovafloxacin is most preferred. Trovafloxacin hasthe following structure:

[0048] Further details regarding the structure, preparation, andphysical properties of Trovafloxacin and other compounds of formula (II)are provided in U.S. Pat. No. 5,164,402. The contents of U.S. Pat. No.5,164,402 relating to the structure, physical properties, andpreparation of the compounds of formula (II) are hereby incorporated inthe present specification by reference.

[0049] The second generation quinolones that may be utilized in thepresent invention include Gatifloxacin and related compounds of thefollowing formula:

[0050] wherein R indicates a hydrogen atom or lower alkyl group, R1indicates a lower alkyl group, R2 indicates a hydrogen atom X indicatesa halogen atom, and Z indicates a halogen atom, piperazino group,N-methylpiperazino group, 3-methylpiperazino group, 3-hydroxypyrrolidinogroup, or pyrrolidino group of the following formula,

[0051] where, n is 0 or 1, R3 indicates a lower alkylgroup, R4 indicatesa hydrogen atom, lower alkyl group, hydroxy-substituted lower alkylgroup or halogenated lower alkyl group and R5 indicates a hydrogen atom,lower alkyl group, acyl group or alkoxycarbonyl group, the hydrates orthe pharmaceutically acceptable acid addition or alklai salts thereof.

[0052] The compound Gatifloxacin is most preferred. Gatifloxacin has thefollowing structure:

[0053] Further details regarding the structure, preparation, andphysical properties of Gatifloxacin and other compounds of formula (III)are provided in U.S. Pat. No. 4,980,470. The contents of U.S. Pat. No.4,980,470 relating to the structure, physical properties, andpreparation of the compounds of formula (III) are hereby incorporated inthe present specification by reference.

[0054] The second generation quinolones that may be utilized in thepresent invention also include Ciprofloxacin, Ofloxacin andLevofloxacin, as well as Grepafloxacin and related compounds of thefollowing formula:

[0055] wherein R1 is a cyclopropyl which may be substituted by 1 to 3 ofsubstituents selected from the group consisting of a C₁-C₆ alkyl and ahalogen atom, a phenyl which may be substituted by 1 to 3 ofsubstituents selected from the group consisting of C₁-C₆ alkoxy, ahalogen atom and hydroxy, a C₁-C₆ alkyl which may be substituted by ahalogen atom, a C₂-C₆ alkanoyloxy or hydroxy, a C₂-C₆ alkenyl orthienyl; R2 is a member selected from the group consisting of a1-piperazinyl group which may have 1 to 3 substituents selected from thegroup consisting of a C₁-C₆ alkyl group, a C₁-C₆ alkanoyl group, aphenyl (C₁-C₆) alkyl group, and a 2-oxo-1,3-dioxolenemethyl group whichmay be substituted by a phenyl group or a C₁-C₆ alkyl group; a1-pyrrolidinyl group which may have 1 to 3 substituents selected fromthe group consisting of an amino group which can have 1 or 2substituents selected from a C₁-C₆ alkyl group and a(C₁-C₆)alkooxy-carbonyl group, an amino(C₁-C₆)alkyl group which may have1 to 2 substituents selected from C₁-C₆ alkyl group and a(C₁-C₆)alkoxy-carbonyl group on the amino moiety, and a C₁-C₆ alkylgroup; a morpholino group which may have 1 to 3 substituents of C₁-C₆alkyl groups; a 1-piperidinyl group which may have 1 to 3 substituentsselected from the group consisting of a C₁-C₆ alkyl group, hydroxy, ahalogen atom and oxo group; and a 1,4-diazobicyclo[4.3.0]nonan-4-ylgroup;

[0056] R3 is a C₁-C₆ alkyl;

[0057] R is hydrogen atom or a C₁-C₆ alkyl; and

[0058] X is a halogen atom, or a pharmaceutically acceptable saltthereof.

[0059] The compound Grepafloxacin has the following structure:

[0060] Further details regarding the structure, preparation, andphysical properties of Grepafloxacin and other compounds of formula (IV)are provided in U.S. Pat. No. 5,563,138. The contents of U.S. Pat. No.5,563,138 relating to the structure, physical properties, andpreparation of the compounds of formula (IV) are hereby incorporated inthe present specification by reference.

[0061] The concentrations of the antibiotics of formula (I) in thecompositions of the present invention will vary depending on theintended use of the compositions (e.g., treatment of existing infectionsor prevention of post-surgical infections), and the relativeantimicrobial activity of the specific antibiotic selected. Theantimicrobial activity of antibiotics is generally expressed as theminimum concentration required to inhibit the growth of a specifiedpathogen. This concentration is also referred to as the “minimuminhibitory concentration” or “MIC”. The term “MIC₉₀” refers to theminimum concentration of antibiotic required to inhibit the growth ofninety percent (90%) of the strains of a species. The concentration ofan antibiotic required to totally kill a specified bacteria is referredto as the “minimum bactericidal concentration” or “MBC”. The minimuminhibitory concentrations of Moxifloxacin, Trovafloxacin, Gatifloxacinand Grepafloxacin, relative to several bacteria commonly associated withotic, ophthalmic, and nasal infections, are provided in the followingtables, wherein the concentrations are expressed as micrograms permilliliter: Microorganism MIC₉₀ Moxifloxacin S. aureus/methicillinsensitive 0.13 S. aureus/methicillin resistant 4.0 S. aureus/quinoloneresistant 4.0 S. epidermidis/methicillin sensitive 0.25 S.epidermidis/methicillin resistant 4.0 S. pneumoniae/penicillin sensitive0.25 S. pneumoniae/penicillin resistant 0.25 P. aeruginosa 8.0 H.influenzae/β-lactamase positive 0.06 H influenzae/β-lactamase negative0.06 M. otitidis 2.0 M. alconae 0.25 Trovafloxacin S. aureus/methicillinsensitive 0.03 S. aureus/methicillin resistant 2.0 S. aureus/quinoloneresistant 4.0 S. epidermidis/methicillin sensitive 0.06 S.epidermidis/methicillin resistant 4.0 S. pneumoniae/penicillin sensitive0.25 S. pneumoniae/penicillin resistant 0.25 P. aeruginosa 2.0 H.influenzae/β-lactamase positive 0.03 H influenzae/β-lactamase negative0.03 Gatifloxacin S. aureus/methicillin sensitive 0.25 S.aureus/methicillin resistant 8.0 S. aureus/quinolone resistant 8.0 S.epidermidis/methicillin sensitive 0.50 S. epidermidis/methicillinresistant 4.0 S. pneumoniae/penicillin sensitive 0.25 S.pneumoniae/penicillin resistant 0.25 P. aeruginosa 2.0 H.influenzae/β-lactamase positive 0.06 H influenzae/β-lactamase negative0.06 Grepafloxacin S. aureus/methicillin sensitive 0.13 S.aureus/methicillin resistant 0.13 S. aureus/quinolone resistant 0.13 S.epidermidis/methicillin sensitive 0.13 S. epidermidis/methicillinresistant 0.13 S. pneumoniae/penicillin sensitive 0.25 S.pneumoniae/penicillin resistant 0.25 P. aeruginosa 8.0 H.influenzae/β-lactamase positive 0.008 H influenzae/β-lactamase negative0.008

[0062] As indicated above, the present invention is based in part on theidentification of two bacterial species that are believed to act aspathogens in acute otitis externa infections, Microbacterium otitidisand Microbacterium alconae. These bacteria belong to the class known as“coryneforms” or “diphtheroids”. Bacteria belonging to this class havebeen previously identified as being present both in healthy ears and inears afflicted with acute otitis externa infections. However, prior tothe present invention, there had been no species-level identification ofthe coryneform bacteria present either in healthy ears or infected ears,nor had there been any attempt to eradicate the pathogenic speciespresent in acute otitis extema infections with antibiotic therapy keyedto those species. The present inventors have now identified two speciesof coryneform bacteria as being present in acute otitis externainfections, and have determined that quinolone antibiotics, particularlythird generation quinolones such as Moxifloxacin, are very effective ineradicating these species.

[0063]Microbacterium otitidis and Microbacterium alconae have also beendiscovered to be pathogens in infections of ophthalmic tissues, such asconjunctivitis and blepharitis. The compositions of the presentinvention are therefore particularly useful in treating ophthalmicinfections involving one or both of these species.

[0064] The bacterial species referred to above were identified as aresult of research conducted on specimens obtained from 2,122 earsafflicted with acute otitis extema infections and 82 healthy ears.Coryneform bacteria of some type were isolated from 10 to 30% of theseears overall; the incidence of finding this class of bacteria presentvaried depending on the season when the specimen was taken. Althoughcoryneform bacteria have been identified previously in both healthy andinfected ears, the present inventors have discovered that the coryneformbacteria present in healthy ears and in acute otitis externa ears aredifferent. In the acute otitis extema ears, 80% of the coryneformbacteria identified belong to the genus Microbacterium, while in thehealthy ears, 90% of the coryneform bacteria identified belong to thegenus Turicella.

[0065] The present inventors have also discovered that the coryneformbacteria found in acute otitis extema patients include two species thathave not previously been identified. These species are now identified asMicrobacterium sp. nov. otitidis and Microbacterium sp. nov. alconae.These names for the species have been assigned by the inventors, buthave not yet been officially published. The names utilized for thesespecies below are “Microbacterium otitidis” (sometimes abbreviated as“M. otitidis”) and “Microbacterium alconae” (sometimes abbreviated as“M. alconae”), respectively.

[0066] In two thirds of the cases where M. otitidis or M. alconaeisolates were identified as being present, these species were the onlytype of bacteria recovered. Moreover, these species were not recoveredfrom healthy ears. These findings lead to the conclusion that M.otitidis and M. alconae are pathogens in acute otitis externa. That is,these species were either largely or totally responsible for the acuteotitis externa infections in the ears from which they were isolated. Theabove-cited findings are believed to represent the first frequentassociation of the genus Microbacterium with a human infectious disease,namely, acute otitis externa. The two new Microbacterium species thathave been discovered to be pathogens in acute otitis externa aredescribed in greater detail below.

[0067] Both new species can be distinguished from the 27 recognizedspecies of Microbacterium phenotypically and genetypically.Genetypically, M. otitidis is most closely related to M. hominis, whileM. alconae is most closely related to M. maritypicum and M.liquefaciens.

[0068] The two new Microbacterium species have been characterized fortaxomonic purposes using DNA methods as well as phenotypic methods. Thesequencing of the 16S rRNA gene showed that both sets of strainsbelonged to the genus Microbacterium, although the sequence differencesfrom established Microbacterium species were significant enough tosuggest novel species. Automated ribotyping patterns further clarifiedthe relationships (similarities and differences) with knownMicrobacterium species. These relationships are shown in FIG. 1. Theabove-cited analyses support the categorization of these bacteria as newspecies.

[0069] Both species of Microbacterium grow optimally at 28-30° C. The M.otitidis isolates grow up to 37° C., while the M. alconae isolates growup to 35° C. The optimal growth temperature at 28-30° C. is typical forbacteria that are normally found in water and soil.

[0070] Phenotypically, the M. otitidis isolates are most easilydistinguished from M. hominis by their inability tometabolize:1)N-acetyl-D-glucosamine,2)3-methyl glucose,3)alaninamide, or4)L-serine. The isolates of M. alconae can be distinguished from M.liquefaciens by their ability to metabolize:1) amygdalin,2)D-mannitol,3)D-melezitose,4)palatinose,5)D-psicose,6)salicin,7)D-sorbitol,8)D-xylose,or 9) p-hydoxyphenyl acetic acid. Also, M. alconae can be distinguishedfrom M. maritypicum by their ability to metabolize:1)amygdalin or2)D-xylose, and can be distinguished from M. maritypicum by theirinability to metabolize:1)L-fucose.

[0071] Analysis of cellular fatty acids for the M. otitidis isolatesshowed the three major fatty acids to be:1)17:0anteiso-60%,2)15:0anteiso-26%, and 3)16:0 iso-11%. Analysis of the M. alconae isolates showed thethree major fatty acids to be:1)15:0 anteiso-55%,2)17:0anteiso-23%,and3)16:0iso-11%.

[0072] The appropriate antibiotic concentration for ophthalmiccompositions will generally be an amount of one or more antibiotics offormula (I) sufficient to provide a concentration in the aqueous humorand lacrimal fluid of the eye equal to or greater than the MIC₉₀ levelfor the selected antibiotic(s), relative to gram-negative andgram-positive organisms commonly associated with ophthalmic infections.The appropriate concentration for otic and nasal compositions willgenerally be an amount of one or more antibiotics of formula (I)sufficient to provide a concentration in the infected tissues equal toor greater than the MIC₉₀ level for the selected antibiotic(s), relativeto gram-negative and gram-positive organisms commonly associated withotic or nasal infections. Such amounts are referred to herein as “anantimicrobial effective amount”. The compositions of the presentinvention will typically contain one or more compounds of formula (I) ina concentration of from about 0.1 to about 1.0 percent by weight (“wt.%”) of the compositions.

[0073] The compositions of the present invention may also contain one ormore anti-inflammatory agents. The anti-inflammatory agents utilized inthe present invention are broadly classified as steroidal ornon-steroidal. The preferred steroidal anti-inflammatory agents areglucocorticoids.

[0074] The preferred glucocorticoids for ophthalmic and otic use includedexamethasone, loteprednol, rimexolone, prednisolone, fluorometholone,and hydrocortisone. The preferred glucocorticoids for nasal use includemometasone, fluticasone, beclomethasone, flunisolide, triamcinolone andbudesonide.

[0075] The dexamethasone derivatives described in U.S. Pat. No.5,223,493 (Boltralik) are also preferred steroidal anti-inflammatoryagents, particularly with respect to compositions for treatingophthalmic inflammation. The following compounds are especiallypreferred:

[0076] These compounds are referred to herein as “21-ether derivativesof dexamethasone”. The 21-benzyl ether derivative (i.e., compoundAL-2512) is particularly preferred.

[0077] The preferred non-steroidal anti-inflammatory agents are:prostaglandin H synthetase inhibitors (Cox I or Cox II), also referredto as cyclooxygenase type I and type II inhibitors, such as diclofenac,flurbiprofen, ketorolac, suprofen, nepafenac, amfenac, indomethacin,naproxen, ibuprofen, bromfenac, ketoprofen, meclofenamate, piroxicam,sulindac, mefanamic acid, diflusinal, oxaprozin, tolmetin, fenoprofen,benoxaprofen, nabumetome, etodolac, phenylbutazone, aspirin,oxyphenbutazone, NCX-4016, HCT-1026, NCX-284, NCX-456, tenoxicam andcarprofen; cyclooxygenase type II selective inhibitors, such as NS-398,vioxx, celecoxib, P54, etodolac, L-804600 and S-33516; PAF antagonists,such as SR-27417, A-137491, ABT-299, apafant, bepafant, minopafant,E-6123, BN-50727, nupafant and modipafant; PDE IV inhibitors, such asariflo, torbafylline, rolipram, filaminast, piclamilast, cipamfylline,CG-1088, V-11294A, CT-2820, PD-168787, CP-293121, DWP-205297, CP-220629,SH-636, BAY-19-8004, and roflumilast; inhibitors of cytokine production,such as inhibitors of the NFkB transcription factor; or otheranti-inflammatory agents known to those skilled in the art.

[0078] The concentrations of the anti-inflammatory agents contained inthe compositions of the present invention will vary based on the agentor agents selected and the type of inflammation being treated. Theconcentrations will be sufficient to reduce inflammation in the targetedophthalmic, otic or nasal tissues following topical application of thecompositions to those tissues. Such an amount is referred to herein as“an anti-inflammatory effective amount”. The compositions of the presentinvention will typically contain one or more anti-inflammatory agents inan amount of from about 0.01 to about 1.0 wt.%.

[0079] The compositions are typically administered to the affectedophthalmic, otic or nasal tissues by topically applying one to fourdrops of a sterile solution or suspension, or a comparable amount of anointment, gel or other solid or semisolid composition, one to four timesper day. However, the compositions may also be formulated as irrigatingsolutions that are applied to the affected ophthalmic, otic or nasaltissues during surgical procedures.

[0080] The ophthalmic, otic and nasal compositions of the presentinvention will contain one or more compounds of formula (I) andpreferably one or more anti-inflammatory agents, in pharmaceuticallyacceptable vehicles. The compositions will typically have a pH in therange of 4.5 to 8.0. The ophthalmic compositions must also be formulatedto have osmotic values that are compatible with the aqueous humor of theeye and ophthalmic tissues. Such osmotic values will generally be in therange of from about 200 to about 400 milliosmoles per kilogram of water(“mOsm/kg”), but will preferably be about 300 mOsm/kg.

[0081] Ophthalmic, otic and nasal pharmaceutical products are typicallypackaged in multidose form. Preservatives are thus required to preventmicrobial contamination during use. Suitable preservatives include:polyquatemium-1, benzalkonium chloride, thimerosal, chlorobutanol,methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium,sorbic acid, or other agents known to those skilled in the art. The useof polyquaternium-1 as the antimicrobial presevative is preferred.Typically such preservatives are employed at a level of from 0.001% to1.0% by weight.

[0082] The solubility of the components of the present compositions maybe enhanced by a surfactant or other appropriate co-solvent in thecomposition. Such co-solvents include polysorbate 20, 60, and 80,polyoxyethylene/polyoxypropylene surfactants (e.g., Pluronic F-68, F-84and P-103), cyclodextrin, or other agents known to those skilled in theart. Typically such co-solvents are employed at a level of from 0.01% to2% by weight.

[0083] The use of viscosity enhancing agents to provide the compositionsof the invention with viscosities greater than the viscosity of simpleaqueous solutions may be desirable to increase ocular absorption of theactive compounds by the target tissues or increase the retention time inthe eye, ear or nose. Such viscosity building agents include, forexample, polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose,hydroxy propyl methylcellulose, hydroxyethyl cellulose, carboxymethylcellulose, hydroxy propyl cellulose or other agents know to thoseskilled in the art. Such agents are typically employed at a level offrom 0.01% to 2% by weight.

[0084] The following examples are provided to further illustrate theophthalmic, otic and nasal compositions of the present invention.Ophthalmic/Otic/Nasal Solution Ingredient Amount (wt. %) Moxifloxacin0.35 Sodium Acetate 0.03 Acetic Acid 0.04 Mannitol 4.60 EDTA 0.05Benzalkonium Chloride 0.006 Water q.s. 100

[0085] Ophthalmic/Otic/Nasal Suspension Ingredient Amount (wt. %)Moxifloxacin 0.3 Dexamethasone, Micronized USP 0.10 BenzalkoniumChloride 0.01 Edetate Disodium, USP 0.01 Sodium Chloride, USP 0.3 SodiumSulfate, USP 1.2 Tyloxapol, USP 0.05 Hydroxyethylcellulose 0.25 SulfuricAcid and/or q.s. for pH adjustment Sodium Hydroxide, NF to 5.5 PurifiedWater, USP q.s. to 100

[0086] Ophthalmic Ointment Ingredient Amount (wt. %) Moxifloxacin 0.35Mineral Oil, USP 2.0  White petrolatium, USP q.s 100

[0087] Ophthalmic Ointment Ingredient Amount (wt. %) Moxifloxacin 0.3Fluorometholone Acetate, USP 0.1 Chlorobutanol, Anhydrous, NF 0.5Mineral Oil, USP 5   White Petrolatum, USP q.s. 100

[0088] The following example is provided to illustrate the activity ofthe compounds of formula (I) against the new Microbacterium speciesdescribed above.

Example 5

[0089] The in vitro activity of Moxifloxacin against Microbacteriumotitidis and Microbacterium alconae was determined using conventionalagar and broth dilution methods, such as those described in NCCLSDocument M7-A4, entitled “Methods for Dilution AntimicrobialSusceptability Tests for Bacteria That Grow Aerobically” (4^(th)Edition). The activity levels were determined as MIC (minimuminhibitory concentration) values. In order to compare the activity ofthe compounds of the present invention to other antibiotics, MIC valuesfor representatives quinolones, aminoglycosides, β-lactams and othertypes of antibiotics were also determined. The results of thesedeterminations are set forth in the table below: Activity ofMoxifloxacin and Other Selected Antibiotics Against New MicrobacteriumSpecies Microbacterium otitidis Microbacterium alconae Isolate Number→MCC MCC MCC MCC MCC MCC MCC MCC MCC MCC Antibiotic ↓ 10647 10810 1099011495 11676 11316 11558 11639 11653 11699 Quinolone Ciprofloxacin 32 3232 32 32 1.0 1.0 1.0 2.0 2.0 Moxifloxacin 2.0 2.0 2.0 2.0 2.0 0.25 0.250.25 0.25 0.25 Ofloxacin 16 32 8.0 16 8.0 4.0 4.0 4.0 4.0 4.0Aminoglycosides Tobramycin 32 4.0 4.0 4.0 16 16 16 16 16 16 Gentamicin8.0 4.0 4.0 16 4.0 2.0 2.0 2.0 2.0 2.0 Neomycin 8.0 2.0 2.0 8.0 2.0 1.01.0 1.0 1.0 1.0 B-Lactams Oxacillin 2.0 4.0 2.0 4.0 2.0 8.0 16 32 32 32Other Antibiotics Erythromycin 0.03 0.03 0.03 0.03 0.03 1.0 2.01 2.00.50 0.50 Clindamycin 0.03 0.03 0.03 0.03 0.03 4.0 4.0 4.0 4.0 4.0Tetracycline 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 Chloramphenicol 1.01.0 1.0 1.0 1.0 16 16 16 16 16 Polymyxin B 1040 260 260 1040 16 32.532.5 16 16 16

[0090] The letters “MCC” in the table above stand for “MicrobiologyCulture Collection”. The MCC numbers (e.g., “MCC 10647”) representseparate clinical isolates of the two Microbacterium species tested. Thefigures set forth in the table are the minimum inhibitory concentrationsfor each compound, relative to the respective isolates of the twoMicrobacterium species, expressed as micrograms per milliliter.

[0091] The invention has been described herein by reference to certainpreferred embodiments. However, as obvious variations thereon willbecome apparent to those skilled in the art, the invention is not to beconsidered as limited thereto.

what is claimed is:
 1. A topical pharmaceutical composition for treatingacute otitis extema infections or ophthalmic infections attributable toa Microbacterium species selected from the group consisting ofMicrobacterium otitidis and Microbacterium alconae, comprising anantimicrobial effective amount of a quinolone antibiotic and apharmaceutically acceptable vehicle therefor.
 2. A composition accordingto claim 1, wherein the composition further comprises an effectiveamount of an antiinflammatory compound.
 3. A composition according toclaim 1, wherein the quinolone antibiotic comprises a third generationquinolone.
 4. A composition according to claim 3, wherein the thirdgeneration quinolone comprises Moxifloxacin.
 5. A composition accordingto claim 4, wherein the composition further comprises an effectiveamount of an antiinflammatory compound.
 6. A composition according toclaim 5, wherein the antiinflammatory compound comprises dexamethasone.7. A composition according to claim 1, wherein the quinolone antibioticcomprises Gatifloxacin.
 8. A method of treating acute otitis externainfections or ophthalmic infections attributable to a Microbacteriumspecies selected from the group consisting of Microbacterium otitidisand Microbacterium alconae, which comprises instilling a therapeuticallyeffective amount of the composition of claim 1 in the affected ear oreye.
 9. A topical pharmaceutical composition for treating otic,ophthalmic or nasal infections attributable to a Microbacterium speciesselected from the group consisting of Microbacterium otitidis andMicrobacterium alconae, comprising an antimicrobial effective amount ofa quinolone antibiotic and a pharmaceutically acceptable vehicletherefor.
 10. A composition according to claim 9, wherein thecomposition further comprises an effective amount of an antiinflammatorycompound.
 11. A composition according to claim 9, wherein the quinoloneantibiotic comprises a third generation quinolone.
 12. A compositionaccording to claim 11, wherein the third generation quinolone comprisesMoxifloxacin.
 13. A composition according to claim 12, wherein thecomposition further comprises an effective amount of an antiinflammatorycompound.
 14. A composition according to claim 13, wherein theantiinflammatory compound comprises dexamethasone.
 15. A compositionaccording to claim 9, wherein the composition comprises Gatifloxacin.